Erythroid differentiation of myeloblast induced by gilteritinib in relapsed FLT3-ITD–positive acute myeloid leukemia

Yun, Hyun Don; Nathan, Sunita; Larson, Melissa L.; Hussain, Mohammad Junaid; Katz, Deborah; Varma, Ankur; Miller, Ira; Üstün, Celalettin

doi:10.1182/bloodadvances.2019000775

Cited by 11 publications

(13 citation statements)

References 15 publications

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Section: Discussionsupporting

confidence: 91%

“…Since red blood cells and megakaryocytes arise from the megakaryocyte-erythroid progenitor and share many regulators including the transcription factors during hematopoiesis (37), our findings are likely similar to a report by Yun et al (32). Hyperactive Flt3-ITD activates downstream STAT5A/B transcription factors, which regulate gene expression in conjunction with other transcriptional regulators and epigenetic modifiers such as EZH2, TET1/2, and DNMT3A (reviewed in Wingelhofer et al (38)).…”

Section: Discussionsupporting

confidence: 89%

“…Both patterns can show relatively stable total marrow cellularity to hypocellular marrow, but numbers of E and Mk were unaffected or showed relative hypoplasia. In contrary, rebound erythroid differentiation was also reported in some cases (32). While the mechanistic underpinnings of such diversified reports remain unclear and is likely multifactorial, it is worth noting that the pharmacokinetic profile of gilteritinib is notable for its large volume of distribution (Vd) with the population estimated central and peripheral Vd of 1,092 and 1,100 L, respectively.…”

Section: Discussionmentioning

confidence: 99%

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Megakaryocytic Expansion in Gilteritinib-Treated Acute Myeloid Leukemia Patients Is Associated With AXL Inhibition

et al. 2020

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Numerous recurrent genetic mutations are known to occur in acute myeloid leukemia (AML). Among these common mutations, Fms-like tyrosine kinase 3 remains as one of the most frequently mutated genes in AML. We observed apparent marrow expansion of megakaryocytes in three out of six patients with Flt3-mutated AML following treatment with a recently FDA-approved Flt3 inhibitor, gilteritinib which possesses activity against internal tandem duplication and tyrosine kinase domain Flt3 mutations and also inhibits tyrosine kinase AXL. To assess whether biopsy findings can be attributed to promotion of megakaryocytic (Mk) differentiation with gilteritinib, we devised a cellular assay by overexpressing double mutated Flt3-ITDY591F/Y919F in chronic myeloid leukemia cell line K562 to study Mk differentiation in the presence of Flt3 and AXL inhibitors with non-mutually exclusive mechanisms. These experiments demonstrated the lack of direct effect Flt3 inhibitors gilteritinib and quizartinib on megakaryocytic differentiation at either transcriptional or phenotypic levels, and highlighted antileukemic effects of AXL receptor tyrosine kinase inhibitor and its potential role in megakaryocytic development.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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Megakaryocytic Expansion in Gilteritinib-Treated Acute Myeloid Leukemia Patients Is Associated With AXL Inhibition

et al. 2020

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“…A secondary clone mutated exclusively at the DNMT3A locus exhibits comparable CD33 expression and resides mainly in the Blast 1 and monocytic clusters (62.5% and 27.7% of DNMT3A mut cells, respectively). At remission, the same DNMT3A mut clone is identified but with decreased CD33 expression and a primarily monocytic immunophenotype (92.7% of differentiation of blasts in a case of leukemia treated with gilteritinib, which is in agreement with a recent study 32 , and contrasts with a prior report of gilteritinib-induced terminal differentiation towards a myeloid fate 31 . However, a larger patient cohort will be necessary to fully characterize the extent of erythroid differentiation in gilteritinib treatment response.…”

Section: Flt3 Inhibitor Therapy Induces Erythroid Differentiation In supporting

confidence: 88%

Joint profiling of DNA and proteins in single cells to dissect genotype-phenotype associations in leukemia

Demaree

Delley

Vasudevan

et al. 2020

Preprint

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2Current leukemia therapies target cancer cells with specific phenotypes or genotypes, but this 3 assumes that either genomic mutations or immunophenotypes alone serve as faithful proxies for 4 treatment response 1 . Moreover, the heterogeneity inherent to all cancers, including leukemias, 5 makes direct mapping of genotype-phenotype relationships challenging 2,3 . Here, we present a 6 method to genotype and phenotype single cells at high throughput, allowing direct characterization 7 of proteogenomic states on tens of thousands of cancer cells rapidly and cost efficiently. Using the 8 approach, we analyze the disease of three leukemia patients over multiple treatment timepoints 9 and recurrences. We observe complex genotype-phenotype dynamics and extensive decoupling of 10 the relationships over disease progression and response to therapy, illustrating the subtlety of the 11 disease process and the inability to use genotypes as direct proxies for phenotypes. Our technology 12 has enabled the first rigorous test of the prevailing paradigm that treatment of a disease phenotype 13 is equivalent to treatment of its underlying genotype. More broadly, our results highlight the power 14 of single-cell multiomic measurements to resolve complex biology in heterogeneous populations, 15 and illustrate how this information can be used to inform treatment. We thus expect that our 16 methodology will find broad application to study proteogenomic tumor landscapes across cancers 17 and will support the next generation of immunotherapy. 18 19 20 Main 21 22 42 aberrations such as single nucleotide polymorphisms (SNPs) and gene fusions 13 . Single-cell RNA 43 sequencing (scRNA-seq) has emerged as a potentially valuable approach for genotype-phenotype 44 linkage because it is cost effective and scalable 3,10,14,15 . The mRNA sequences provide genotype 45 information 15,16 while their counts relate phenotype 17-21 . Moreover, modern approaches are 46 extremely high throughput, allowing characterization of thousands of cells. Nevertheless, 47

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“…Thus, for our final case, we analyzed a patient treated with gilteritinib, a FLT3 inhibitor therapy reported to promote in vivo differentiation of myeloid blasts. This treatment is thought to disperse distinct genotypes into multiple immunophenotypes, although the terminal lineage of the cells remains poorly understood [30][31][32] . Accordingly, we hypothesized DAb-seq permits tracking of immunophenotypic dispersal and confirmation of their terminal hematopoietic lineage.…”

Section: Resultsmentioning

confidence: 99%

Joint profiling of DNA and proteins in single cells to dissect genotype-phenotype associations in leukemia

et al. 2021

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Studies of acute myeloid leukemia rely on DNA sequencing and immunophenotyping by flow cytometry as primary tools for disease characterization. However, leukemia tumor heterogeneity complicates integration of DNA variants and immunophenotypes from separate measurements. Here we introduce DAb-seq, a technology for simultaneous capture of DNA genotype and cell surface phenotype from single cells at high throughput, enabling direct profiling of proteogenomic states in tens of thousands of cells. To demonstrate the approach, we analyze the disease of three patients with leukemia over multiple treatment timepoints and disease recurrences. We observe complex genotype-phenotype dynamics that illustrate the subtlety of the disease process and the degree of incongruity between blast cell genotype and phenotype in different clinical scenarios. Our results highlight the importance of combined single-cell DNA and protein measurements to fully characterize the heterogeneity of leukemia.

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Erythroid differentiation of myeloblast induced by gilteritinib in relapsed FLT3-ITD–positive acute myeloid leukemia

Abstract: CD. Evidence for clinical differentiation and differentiation syndrome in patients with acute myeloid leukemia and IDH1 mutations treated with the targeted mutant IDH1 inhibitor,

Cited by 11 publications

References 15 publications

Megakaryocytic Expansion in Gilteritinib-Treated Acute Myeloid Leukemia Patients Is Associated With AXL Inhibition

Megakaryocytic Expansion in Gilteritinib-Treated Acute Myeloid Leukemia Patients Is Associated With AXL Inhibition

Joint profiling of DNA and proteins in single cells to dissect genotype-phenotype associations in leukemia

Joint profiling of DNA and proteins in single cells to dissect genotype-phenotype associations in leukemia

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